Clinical Investigations of CAR-T Cell Therapy for Solid Tumors

Chen, Kun; Wang, Shuhang; Qi, Dan; Ma, Peiwen; Fang, Yuan; Jiang, Ning; Wu, Erxi; Li, Ning

doi:10.3389/fimmu.2022.896685

Cited by 10 publications

(10 citation statements)

References 73 publications

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“…Cell therapies are in common clinical practice for certain indications, such as islet cell transplants, and are also being aggressively developed in other areas of medicine, such as T-cell therapy of tumor. 66 Take T-cell therapy for tumor treatment as an example, chimeric antigen receptor (CAR) T cells are genetically engineered T cells to express a receptor for the recognition of the particular surface marker that has given rise to advances in the treatment of blood disorders. However, their efficacy in solid tumor treatment has not yet been supported.…”

Section: Discussionmentioning

confidence: 99%

Surface-Engineered Monocyte Immunotherapy Combined Graphene Quantum Dots Effective Against Solid Tumor Targets

Xia¹,

Tang²,

Li³

et al. 2023

IJN

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The immunosuppressive tumor microenvironment (TME) of solid tumors inhibits most drug delivery system-based nanomaterials from achieving deep penetration in tumor tissue and interferes with T cell activity in terms of differentiation and exhaustion, which is becoming a critical therapy hurdle for solid tumors. Therefore, developing a therapeutic strategy with abilities of rapid establishment of tumor-targeted cells, elimination of immune obstacles, and enhanced active immunization is very important, while is still a big challenge. Methods: A new strategy was explored to enhance immune therapy via the conjugation of microRNA155 (miR) to the surface of therapeutic monocyte with graphene quantum dots (GQDs). Results: TME was reversed using surface-engineered monocyte immunotherapy via reprogramming pro-tumoral M2 TAMs into antitumor M1, and thus tumor elimination was dramatically enhanced. Conclusion: Such a surface-engineered monocyte immunotherapy has been demonstrated to be well tolerated to intravenous administration and bio-compatible, showing the potential to be extended for the solid tumor treatment.

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Section: Discussionmentioning

confidence: 99%

Surface-Engineered Monocyte Immunotherapy Combined Graphene Quantum Dots Effective Against Solid Tumor Targets

Xia¹,

Tang²,

Li³

et al. 2023

IJN

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“…Recent years, chimeric antigen receptor (CAR) T-cell has been designed to recognize and eliminate tumor cells via bridging between tumor-associated antigens (TAAs) and has become a sound momentum of therapeutic potential in hematological malignancies clinical practice, particularly CD19 CAR-T cells therapy 3 - 7 . However, several CAR-T cells have been described in treatment of late-stage multifocal, bulky solid tumors in recent clinical studies 8 , 9 , the responses are not consistent and less favorable, mainly for specific and homogeneously expressed targets, and the existing strong heterogeneity of complex components within solid tumor 10 , 11 , Therefore, new and active CAR-T cells with reliable safety and significant improvement in solid tumor treatments are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

A dendritic/tumor fusion cell vaccine enhances efficacy of nanobody-based CAR-T cells against solid tumor

Sun,

Ding,

Gao

et al. 2023

Theranostics

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Background: Chimeric antigen receptor (CAR) T-cell therapy is practical in treating cancers of hematopoietic origin, but of that in solid tumors compromises efficacy for the loss of the antigen recognized by the CAR. However, dendritic cell (DC)/tumor fusion vaccines present a spectrum of known or unknown tumor antigens to stimulate T cell expansion and enhanced T cell response. Developing a new strategy of enhanced nanobody-based CAR-T (Nb-CAR-T) cells antitumor activity by DC/tumor fusion vaccines stimulation would provide guidance for more effective CAR-T cell therapies. Methods: Considering the therapeutic potential of nanobody (Nb), we first screened EGFRvIII Nb, then constructed and verified the function of EGFRvIII Nb-CAR-T cells in vitro and in vivo . We further combined DC/tumor fusion vaccines to boost EGFRvIII Nb-CAR-T cells antitumor effect, which was evaluated in vitro Nb-CAR-T cell function and in the tumor-bearing xenograft mouse models. Results: We had for the first time successfully selected EGFRvIII Nb for the generation of the novel EGFRvIII Nb-CAR-T cells. Importantly, our results suggested that DC/tumor fusion vaccines stimulate Nb-CAR-T cells response not only in improving T cell proliferation, T cell activation, cytokine secretion and tumor-specific cytotoxicity in vitro , but also significantly reducing tumor burden, prolonging survival and improving Nb-CAR-T cells infiltration. Conclusions: We have innovatively shown that DC/tumor fusion vaccines significantly enhance the efficacy of Nb-CAR-T cells against solid tumors. This new strategy has provided a promising therapeutic platform for promoting the clinical treatment of CAR-T cells therapy.

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“…Here, we evaluated the effect of FAP CAR T-cell pre-treatment on therapeutic efficacy of CAR T-cells targeting tumor-antigens currently under investigation in clinical trials against solid tumors 8, 9 . For this purpose, we selected the tumor associated antigen (TAA) Mesothelin which is overexpressed in most solid tumors including mesothelioma and large sub-sets of ovarian, breast, pancreatic and lung adenocarcinomas.…”

Section: Introductionmentioning

confidence: 99%

“…However, CAR T-cell therapy against solid tumors, which comprise about 90% of the total cancer landscape 7 , has encountered very limited success. Notably, the clinical efficacy of CAR T-cell trials against the top three widely expressed solid tumor targets namely mesothelin, GPC3 and mucin-1 (MUC1) have so far been met with low to middling success 8 .…”

Section: Introductionmentioning

confidence: 99%

Stromal depletion by TALEN-edited universal hypoimmunogenic FAP-CAR T cells enables infiltration and anti-tumor cytotoxicity of tumor antigen-targeted CAR-T immunotherapy

Das

Valton

Duchâteau

et al. 2023

Preprint

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Adoptive cell therapy based on chimeric antigen receptor-engineered T (CAR-T) cells has proven to be lifesaving for many cancer patients. However, its therapeutic efficacy has so far been restricted to only a few malignancies, with solid tumors proving to be especially recalcitrant to efficient therapy. Poor intra-tumor infiltration by T cells and T cell dysfunction due to a desmoplastic, immunosuppressive microenvironment are key barriers for CAR T-cell success against solid tumors. Cancer-associated fibroblasts (CAFs) are critical components of the tumor stroma, evolving specifically within the tumor microenvironment in response to tumor cell cues. The CAF secretome is a significant contributor to the extracellular matrix and a plethora of cytokines and growth factors that induce immune suppression. Together they form a physical and chemical barrier which induces a T cell-excluding cold TME. CAF depletion in stroma rich solid tumors can thus provide an opportunity to convert immune evasive tumors susceptible to tumor-antigen CAR T-cell cytotoxicity. Using our TALEN-based gene editing platform we engineered non-alloreactive, immune evasive CAR T-cells (termed UCAR T-cells) targeting the unique CAF marker Fibroblast Activation Protein, alpha (FAP). In an orthotopic mouse model of triple-negative breast cancer (TNBC) composed of patient derived-CAFs and tumor cells, we demonstrate the efficacy of our engineered FAP UCAR T-cells in CAF depletion, reduction of desmoplasia and successful tumor infiltration. Furthermore, while previously resistant, pre-treatment with FAP UCAR T-cells now sensitized these tumors to Mesothelin (Meso) UCAR T-cell infiltration and anti-tumor cytotoxicity. Combination therapy of FAP UCAR, Meso UCAR T cells and the checkpoint inhibitor anti-PD-1 significantly reduced tumor burden and prolonged mice survival. Our study thus proposes a novel treatment paradigm for successful CAR-T immunotherapy against stroma-rich solid tumors.

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Clinical Investigations of CAR-T Cell Therapy for Solid Tumors

Cited by 10 publications

References 73 publications

Surface-Engineered Monocyte Immunotherapy Combined Graphene Quantum Dots Effective Against Solid Tumor Targets

Surface-Engineered Monocyte Immunotherapy Combined Graphene Quantum Dots Effective Against Solid Tumor Targets

A dendritic/tumor fusion cell vaccine enhances efficacy of nanobody-based CAR-T cells against solid tumor

Stromal depletion by TALEN-edited universal hypoimmunogenic FAP-CAR T cells enables infiltration and anti-tumor cytotoxicity of tumor antigen-targeted CAR-T immunotherapy

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